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Nano Today (2014) xxx, xxx—xxx
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: www.elsevier.com/locate/nanotoday
REVIEW
Surgical materials: Current challenges and
nano-enabled solutions
Nasim Annabi a,b,c, Ali Tamayol a,b, Su Ryon Shin a,b,c,
Amir M. Ghaemmaghami d, Nicholas A. Peppas e,
Ali Khademhosseini a,b,c,e,f,g,∗
a
Center for Biomaterials Innovation, Department of Medicine, Brigham and Women’s Hospital,
Harvard Medical School, Boston, MA, USA
b
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology,
Cambridge, MA, USA
c
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
d
Division of Immunology, School of Life Sciences, Faculty of Medicine and Health Sciences, University of
Nottingham, United Kingdom
e
Department of Biomedical Engineering, Department of Chemical Engineering and College of Pharmacy,
The University of Texas at Austin, Austin, TX, USA
f
Department of Maxillofacial Biomedical Engineering and Institute of Oral Biology, School of Dentistry,
Kyung Hee University, Seoul 130-701, Republic of Korea
g
Department of Physics, King Abdulaziz University, Jeddah 21569, Saudi Arabia
Received 18 May 2014; received in revised form 28 July 2014; accepted 1 September 2014
KEYWORDS
Nano-enabled
surgical materials;
Sealants;
Tissue adhesives;
Hemostatic agents;
Antibacterial
bioadhesives
Abstract Surgical adhesive biomaterials have emerged as substitutes to sutures and staples
in many clinical applications. Nano-enabled materials containing nanoparticles or having a distinct nanotopography have been utilized for generation of a new class of surgical materials
with enhanced functionality. In this review, the state of the art in the development of conventional surgical adhesive biomaterials is critically reviewed and their shortcomings are outlined.
Recent advancements in generation of nano-enabled surgical materials with their potential
future applications are discussed. This review will open new avenues for the innovative development of the next generation of tissue adhesives, hemostats, and sealants with enhanced
functionality for various surgical applications.
© 2014 Elsevier Ltd. All rights reserved.
∗ Corresponding author at: Center for Biomaterials Innovation, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical
School, Boston, MA, USA. Tel.: +1 617 768 8395.
E-mail addresses: [email protected], [email protected] (A. Khademhosseini).
http://dx.doi.org/10.1016/j.nantod.2014.09.006
1748-0132/© 2014 Elsevier Ltd. All rights reserved.
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Introduction
Reconnection of injured tissues after surgery is essential to
restore their structure and function. Sutures, wires, and staples are widely used for this purpose, i.e., mostly to hold the
tissues in close proximity for fast healing, to resist applied
mechanical loads, and to stop body fluid leakages after
surgery. Despite their common use in clinic, these methods are not suitable for many procedures, in particular for
applications that require preventing body fluid and air leakages. In addition, complete sealing of incisions by sutures
generally requires high level of training of surgeons and is
particularly challenging for minimally invasive surgeries. In
addition, it is challenging to accurately apply sutures and
staples in the regions of body that are not easy-to-access.
The incision closure procedures using sutures and staples
may also induce additional damage in the surrounding tissues in the surgery site. Surgical adhesive biomaterials have
emerged as attractive alternatives to stapling and suturing
due to their easy application and versatility. These materials can close the incision site more quickly and effectively
compared to sutures, which reduces the risk of infection and
blood loss by the patient [1,2].
Biomaterials can be used for various surgical operations
as tissue adhesives, sealants, and hemostats [3]. Much success has been achieved in hard- and soft-tissue adhesives
with the availability of many commercially available bioadhesive systems [4]. Tissue adhesives are surgical materials
which can be used to adhere two tissues together, hemostats
are mainly used to control bleeding, and sealants act as
a barrier to liquid or air [2]. Surgical materials should
be biocompatible, easy-to-apply, biodegradable, and inexpensive. They should also possess appropriate mechanical
strength and adhesion properties as well as fast curing
capability [5]. Commercially available surgical materials
are formed from natural or synthetic sources, or a combination of both in the form of composites [6]. Commonly
used natural materials for surgical applications include fibrin
[7,8], collagen [9], gelatin [10], and polysaccharides [11]
and their mixtures. Cyanoacrylates [12,13], various dendrimers [14], polyurethanes (PUs) [15], and poly(ethylene
glycol) (PEG) [16] are examples of synthetic surgical materials. Various composite surgical materials have been also
formed by using both natural and synthetic polymers such as
gelatin-resorcinol-formaldehyde (GRF) [17], albumin/PEG
(Progel, Bard Inc.) [18], dextran/(2-hydroxyethyl methacrylate) [19], chitosan/polylysine [20], and PEG/dextran [21].
High cost, limited availability, pro-inflammatory potential, and immunogenicity are some of the limitations
associated with naturally derived surgical materials, which
limit their use in some surgical procedures. Despite having
higher mechanical strength and tissue-bonding properties,
synthetic and composite surgical materials have several
disadvantages including cytotoxicity, chronic inflammation,
low adherence to the wet tissues and, in some cases, long
curing time [6].
Recently, extensive research efforts have been made
to incorporate nanoscale structures and materials in the
design of surgical materials to overcome the aforementioned
challenges and provide the next generation of surgical adhesives. For example, it has been demonstrated that aqueous
solution of nanoparticles can be used to introduce strong
bonding between the tissues without the need for complex in situ polymerization or crosslinking reactions [22].
These particle solutions absorb on the surfaces of tissues
and act as a connector between the tissues. Nanoparticle
solutions can be also used as hemostatic materials to stop
internal bleeding with no requirement for specific preparation or control on polymerization reactions as needed for
polymer-based hemostatic agent [23]. In addition, various
types of nanomaterials have been incorporated into polymer
matrices to introduce new functionalities such as providing
antibacterial activity. In addition, nanoparticles loaded into
surgical materials can improve their adhesion strength and
mechanical properties. In general, the use of nanomaterials
in the design of tissue adhesive has eliminated the requirement for complex in vivo polymerization or crosslinking
reactions and led to the development of easy-to-use tissue adhesives and hemostats with improved functionalities
for clinical applications. Nanomaterial-incorporated tissue
adhesives can address many limitations of currently available tissue adhesives such as toxicity, extensive swelling,
insufficient strength, and complex polymerization process.
They have the potential to be used instead of sutures and
staples in clinical practice, particularly in invasive surgeries
to minimize tissue damage.
More recently, an active area of research has focused on
developing surgical tissue adhesive with specific nanotopography to engineer biomimetic structures inspired by nature.
Nanotopography is deemed as the specific spatiotemporal
coordination and distribution of molecular structures that
provides detailed and desirable structures. The employed
nanotopography can enhance the adhesion force through
the augmentation of contact area and the adhesive van der
Waals and capillary forces. Moreover, these nanopatterns
can be used for creating mechanical interlocking to increase
the required detachment forces [24].
In this work, conventional surgical materials made of
natural and synthetic polymers are critically reviewed
along with their advantages and limitations for surgical
applications. Recent developments in synthesis and characterization of nanomaterial incorporated surgical materials
with hemostatic and antibacterial properties are discussed.
In addition, emerging technologies for generating micro- and
nanoscale topography in tissue adhesives to improve their
adhesion strength are highlighted.
Conventional surgical materials
Wound closure is a key step in the success of various
surgical procedures. Each procedure carries specific risk
factors, which should be addressed by utilization of functional bioadhesive that meet these criteria. For example,
during vascular anastomosis preoperative bleeding from the
surgery site and blood coagulation are among the key risk
factors [25]. Thus, the employed tissue adhesives should
be hemostatic, while possess sufficient mechanical properties to hold the tissue together. Ease of application and
the minimal need for utilization of external devices during the crosslinking process are also important for closing
internal surgery lacerations during operation. However, for
treating traumatic injuries, the wound closure procedure
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Surgical materials
should be quick and minimally invasive [26]. The adhesion strength of the bioadhesive should be high enough to
prevent tissue detachment after treatment. In addition, ideally the mechanical properties of the bioadhesive materials
should mimic the surrounding tissue [27]. The employed tissue adhesive should also form an effective barrier against
external risk factors including bacteria and other pathogens.
In the following sections we will discuss various types of
existing tissue adhesives.
Natural origin surgical materials
Surgical materials based on natural polymers have attracted
significant attention due to their biocompatibility and similarity to the tissue microenvironment [28]. These natural
surgical materials are obtained from biological sources such
as human blood (e.g. fibrin) or formed by chemical crosslinking of various natural polymers including collagen, gelatin,
chitosan, alginate, and chondroitin [29].
Fibrin-based surgical materials are one of the most widely
used glues in clinical applications. They are made from
two main components, fibrinogen and thrombin, with a
small quantity of calcium chloride to form surgical materials with dual applications, hemostatic and sealant [30].
Fibrin is polymerized from the fibrinogen and then a white
fibrin clot is generated with thrombin and CaCl2 . Commercial
fibrin-based surgical materials, such as Evicel (Ethicon Inc.),
Hemaseel APR (Heamacure Corp.), Tisseel (Baxter Healthcare Corp.), and Crosseal (OMRIX Biopharmaceuticals Ltd.)
have been widely used as both hemostatic [31] and sealants
[32]. Despite their advantages including biocompatibility,
fast curing and biodegradability, poor adhesion properties of
fibrin-based glues to the wet tissues and their low mechanical strength under loading make them unsuitable for many
surgical procedures [33,34]. Therefore, for some clinical
applications, fibrin-based surgical glues should be used along
with sutures or staples [35,36]. The use of human-based
fibrin glues also carries the risk of disease transmission
[34,37].
Collagen-based surgical materials are another type of
natural tissue adhesive [38]. The most commonly used
collagen-based surgical materials approved for clinical
applications are Proceed (Fusion Medical Technologies) [39],
a composition of bovine collagen and bovine thrombin, and
CoStasis (Cohesion Technologies, Inc.) [40], which is made
of human plasma, bovine collagen, and thrombin. Similar
to fibrin, collagen-based adhesives have low adhesion and
mechanical strength. Gelatin-based bioadhesives such as
FlosealTM (Fusion Medical Technologies, Inc.) [41], a combination of bovine gelatin and thrombin, have been also
used as hemostatic agents. In another study, photocrosslinkable gelatin sealants with high adhesion strength (more than
100 kPa) and tensile strength (around 2 MPa) were produced
to seal vascular, lung, and gastrointestinal defects [10].
Other crosslinking approaches such as chemical crosslinking using aldehyde and microbial transglutaminase (mTG)
have also been used to form gelatin-based hemostatic adhesives, which can connect tissues in the absence of sutures
[42]. Furthermore, hemostatic materials and tissue adhesives based on a combination of gelatin and poly(L-glutamic
acid) have also been developed [34]. Chitosan-based tissue
3
adhesives are another family of commercially available natural surgical materials for clinical applications [43]. Chitosan
offers both antibacterial and hemostatic characteristics
and has been used in various forms such as powders (e.g.
CeloxTM ) or photocrosslinked hydrogels to stop bleeding from
the arteries [44].
To improve the mechanical properties and adhesion
strength of natural tissue adhesives, composite glues
based on a combination of different natural and synthetic
components have been developed. One example is the
French glue or GRF (GRF glue®), which is a composite
of gelatin/resorcinol and formaldehyde [45,46,17]. Due to
their ability to provide strong covalent bonding to wet tissues using aldehydes groups, GRF glues have been used in
Europe for aortic dissections, liver, urinary tract, and gastrointestinal surgeries. However, the presence of unreacted
aldehydes may cause toxicity, which has limited their use in
North America [45,46,17]. BioGlue (Cryolife Inc.) is another
FDA approved sealants based on a combination of human
albumin and glutaraldehyde [47—50]. Although BioGlue has
been successfully applied for sealing large blood vessels and
aortic dissections, it contains aldehyde that generates safety
concerns for clinical applications.
Synthetic and semi-synthetic surgical materials
Various types of synthetic and semi-synthetic materials such
as cyanoacrylates, PUs, PEG-based dendrimers, and PEG
hydrogels have been used for developing surgical materials
for different clinical applications. These surgical materials
offer strong adhesive properties and mechanical strength.
In addition, their compositions, structures, and physical
properties can be tailored for specific applications. Among
synthetic tissue adhesives, cyanoacrylates have been widely
used for external applications such as closure of skin wounds
due to their fast curing, strong adhesion to tissues, and ease
of use [51]. The synthetic adhesives based on cyanoacrylate are liquid monomers. These monomers can polymerize
rapidly by an anionic mechanism in the presence of water
or blood to form a flexible film that bridges the wounds
and holds the apposed wound edges together. For example, Dermabond (Ethicon Inc.) is a glue based on 2-octyl
cyanoacrylate and has been widely used by surgeons in cosmetic surgery, for closing small lacerations and in skin graft
fixation [52]. However, high price and foreign body reaction
are some of the limitations associated with the use of Dermabond. Other commercially available cyanoacrylate-based
bioadhesives are Trufill n-BCA (Cordis Neurovascular, Inc.), a
combination of tantalum powder and n-butyl cyanoacrylate,
and Glubran2 (GEM s.r.l.), a modified form of n-butyl-2cyanoacrylate [51,53]. These products have shown strong
adhesive and hemostatic properties for various clinical
applications, but they can only be employed for external
use due to their potential toxicity and pro-inflammatory
characteristic upon contacting non-cutaneous surfaces [54].
Another class of synthetic surgical materials is PEGbased sealants, which are mainly composed of chemically
modified linear or branched PEG molecules. Coseal (Cohesion Technologies, Inc.) is a commercially available
PEG-based sealant, composed of two four-arm PEG, one with
glutaryl-succinimidyl ester terminal groups and the other
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one with thiol terminal groups. Upon mixing, covalent bonds
between PEG molecules are formed through the reaction
between thiol groups and the carbonyl groups of the succinimidylester. Coseal has been widely used for sealing suture
lines in vascular grafts [26,54,55].
Duraseal (Covidien Inc.) is another FDA approved PEGbased tissue adhesive, consisting of PEG ester and trilysine
amine solutions [56—58]. Duraseal is commonly used by
neurosurgeons to stop cerebrospinal fluid leakage following
surgeries. A bioresorbable and photocrosslinkable PEGbased sealant, FocalSeal (Genzyme Biosurgery, Inc.), has
been developed for thoracic surgery to stop air leaks [59].
FocalSeal has been also used for wound closure and hemostasis in anastomotic bleeding [16,59,60]. PEG-based sealants
have several advantages including biocompatibility and relatively high adhesion strength. However, high swelling ratio
of PEG-based sealants may cause pressure build up on the
surrounding tissues when applied in closed cavities [61]. In
addition, the use of UV light and long curing time may limit
their clinical applications (e.g. its utilization in hemorrhagic
situations).
Recently, PU-based surgical materials have received
attention because of their strong adhesion to tissues through
the formation of urea bonds [1]. No toxicity has been
reported upon utilization of urethane-based bioadhesives
for renal surgery, pancreatic occlusion, and orthopedic
surgeries. A sprayable PU adhesive, TissuGlu (Cohera Medical Inc.), has been developed for cosmetic procedures
as a resorbable and non-toxic tissue adhesive [62]. Prolonged curing times and the possibility of toxic degradation
products are potential limitations associated with the
utilization of urethane-based materials for clinical applications. Ferreira et al. synthesized biodegradable PU-based
adhesives through the reaction between castor oil and
isophorone diisocyanate (IPDI) or by reaction of polycaprolactone (PCL) diol with IPDI or hexamethylene diisocyanate
(HDI) [63]. Despite significant improvements in the synthesis of biodegradable and biocompatible PU-based surgical
materials, safety concerns still exist for their clinical applications. Recently, Lang et al. developed a hydrophobic
light-activated tissue adhesive (HLAA) for cardiovascular
surgeries [64]. This highly elastic tissue adhesive was formed
by photocrosslinking of poly (glycerol sebacate acrylate)
(PGSA) in the presence of a photoinitiator and UV light.
The result of in vivo tests showed no inflammatory reaction after attaching a HLAA coated patch on the rat heart,
demonstrating the biocompatibility of the engineered HLAA
bioadhesives. In addition, HLAA tissue adhesive was used to
close defects in a pig carotid artery without the use of a
patch. No bleeding was observed after 24 h of implantation
and all animals survived after the procedure. H&E staining
of the carotid arteries exhibited an intact endothelium with
no thrombus formation, demonstrating the suitability of the
HLAA for the repair of vascular defects [64].
One of the limitations of the conventional surgical materials including synthetic glues such as cyanoacrylate or
natural bioadhesives like fibrin is their low adhesion in wet
environments, which limits their applications for internal
use. To address this challenge, scientists have focused on
natural models with high adhesion strength to wet surfaces
such as marine mussel proteins to mimic their adherence
mechanism [65—67].
Mussels (e.g. Mytilus edulis) adhere strongly to underwater surfaces by secreting adhesive materials (byssus)
from their feet [68]. These adhesive materials contain
a bundle of threads with adhesive plaques at the end
of the threads to anchor to wet surfaces. It has been
shown that this strong adhesion in wet environment is
due to the presence of a catechol-containing amino acid
L-3,4-dihydroxyphenylalanine (L-DOPA), which enables the
crosslinking of mussel adhesive proteins through oxidation
of catechol hydroxyl groups to DOPA-quinone [69,70]. The
adhesion mechanism of mussels has been mimicked by many
research groups to develop tissue adhesives with the ability
to adhere to wet surfaces [71,72].
Several researchers initially focused on extraction and
purification of adhesive proteins from mussels [73] or synthesis of recombinant mussel proteins [74]. The extracted
adhesive proteins were crosslinked to enhance adhesion
strength and mechanical properties of the bioadhesives for
various clinical applications [75]. However, the use of complicated extraction processes and low yield (1 gr adhesive
protein from 10,000 mussels) have limited the production
of mussel-derived adhesive proteins [76,77]. To overcome
these limitations, researchers synthesized DOPA-containing
polypeptides [71] or DOPA functionalized polymers [72]. For
example, DOPA-functionalized PEG tissue adhesives were
synthesized by using different oxidation agents such as
horseradish peroxide, mushroom tyrosinase hydrogen peroxide, and sodium periodate [72].
In another study, surgical meshes coated by DOPAfunctionalized PEG and PCL were produced to eliminate
the need for mechanical fixation of the mesh for surgical
repair of soft tissues [78]. More recently, an injectable and
biodegradable citrate-enabled mussel-inspired bioadhesive
(iCMBA) was produced using citric acid, dopamine/L-DOPA,
and PEG [79]. This synthesized tissue adhesive showed
2.5—10 times higher adhesion strength compared to commercial fibrin glues. In vivo studies demonstrated that iCMBA
adhesive could rapidly stop bleeding and close open wounds,
in the absence of stitches or staples, on the dorsum of
a rat model [79]. Mussel-inspired tissue adhesives have
shown several advantages for clinical applications such as
strong adhesion to the wet tissues, biocompatibility, and
biodegradability. Recently, this group of tissue adhesives
have been used for various applications including fixation
of prosthetic meshes [6], extrahepatic islet transplantation
[80], bioadhesives for small intestinal submucosa [81], and
injectable sealants for fetal membrane repair [82,83].
Overall, conventional surgical materials have shown to
possess significant potential in many clinical applications.
However, strong adhesion to wet tissues, biocompatibility, biodegradability, affordable cost, and ease of use are
some of the requirements to be addressed. Various research
groups have focused on engineering multifunctional surgical materials by merging nanotechnology and advanced
biomaterials. For example, one research area has focused
on developing nanomaterial-incorporated surgical materials with hemostatic or antibacterial properties. Recently,
biomimetic nanostructured tissue adhesives with improved
adhesion strength have been also developed. Recent developments in engineering of nano-enabled surgical materials
for various clinical applications are highlighted in the following sections.
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Surgical materials
Nanoparticle incorporated surgical materials
Conventional polymeric tissue adhesives usually require
complex in vivo control of polymerization or crosslinking
reactions. They may also suffer from being toxic, weak,
or ineffective within the wet conditions. Nanoscience and
nanotechnology play an important role in improving the
properties and function of tissue adhesives for clinical applications. For example, nanotechnology enables the use of
nanoparticle solutions as adhesives and hemostatic materials to strongly bind biological tissues together and stop
internal bleeding without the need of using complex in situ
polymerization techniques. It has been shown that surface
chemistry modification of these nanoparticles can enhance
particle adsorption to the tissues and form strong bonding between them [22,23]. In addition, tissue adhesives
with antibacterial capabilities can be formed through the
incorporation of antimicrobial nanoparticles or hemostatic
bioadhesives can be engineered by encapsulation of active
nanoparticles in the adhesives [84]. Novel bioadhesives have
been also developed for controlled drug-delivery [4,85,86].
In this section, recent advances on the application of nanotechnology in designing multifunctional surgical materials
are reviewed. In particular, the use of nanoparticles for
engineering antibacterial and hemostatic bioadhesives is
discussed. Table 1 summarizes some examples of traditional
and nano-enabled adhesive materials with their formulation, adhesion strength, and functionalities.
Hemostatic materials
Hemostatic agents are being increasingly used in various
procedures such as hepatic, cardiovascular, spinal, and
orthopedic surgeries where hemorrhage control is essential
to avoid severe blood loss [87,88]. Suturing is conventionally applied to stop bleeding but it is not effective for
controlling rapid bleeding in many procedures. Therefore,
hemostats are used during surgeries for fast and effective control of bleeding. These hemostatic agents should
be safe, easy-to-apply as well as provide fast blood clotting. Hemostatic materials are classified into two main
categories: mechanical and active agents [29]. Mechanical
hemostatic agents stop bleeding by generating a mechanical barrier to the blood flow and can be used in forms
of sponges, sheets, powders, or particles. Some examples of the commercially available mechanical hemostatic
agents include Gelfoam (bovine gelatin, Baxter Inc.), Instat
(bovine collagen, Ethicon, Inc.), and Surgicel (oxidized
cellulose, Ethicon, Inc.) [61]. Active hemostatic agents
contain active biological components such as thrombin,
which can participate in blood clotting when applied to the
injured sites [29]. Combination of mechanical and active
agents has been shown to enhance the hemostatic efficacy
[61].
Mineral zeolite materials such as QuikClot (Z-Medica,
Wallingford, CT) have had a significant impact on trauma
care in clinical applications [89—91]. Mineral zeolite materials absorb liquid in the wound area, thereby increasing
the concentration of coagulants to induce hemostasis. The
activity of zeolite materials leads to an exothermic reaction in wound bed, which has been addressed by embedding
5
zeolite in a surgical mesh so it can be used as a compress
to absorb water less exothermically by using ion exchange
technique and prehydration [92,93]. Zeolite materials are
inexpensive, stable, easy-to-use, and have shown to have
both hemostatic and antibacterial properties [89]. In a clinical study, QuikClot was found to control bleeding in 92% of
the 103 documented cases with 100% of the cases performed
by first responders [94].
Hemostatic materials can be formed by combining one
or two coagulation cascades or hemostatic proteins including thrombin [95], collagen [96], chitosan [97,98], and fibrin
[4,99] as well as non-protein materials such as oxidized
cellulose [96,100] and PEG [100]. These hemostats have
been used in various forms for surgical applications including
matrix [96,101], patch [102,103] or liquid [95,99]. The major
challenges associated with the clinical use of these hemostatic materials include their high cost and non-effective
bleeding control [104].
To address these challenges, micro and nanoparticles
have been used as hemostatic agents to control blood loss.
For example, in a recent study, cationic hydrogel particles based on N-(3-a-aminopropyl)methacrylamide (APM)
were synthesized via inverse suspension polymerization and
used as hemostatic agents (Figure 1A) [105]. In vitro studies confirmed the formation of blood aggregation, which
was due to the high swelling ratio of the hydrogel particles (>1000%) as well as their high positive charge. The
capability of the engineered particles for rapid hemostasis
in vivo was also demonstrated by using a tail amputation rat
model (Figure 1B and C) and an ovine liver laceration model
(Figure 1D and E) [105].
Some research groups have focused on developing hemostatic materials based on functionalized nanoparticles
capable of aggregating platelets from blood flow [106—109].
For example, Ravikumar et al. created hemostatic nanomaterials through the surface functionalization of liposomes
with 150 nm diameters with three peptides including von
Willebrand factor (vWF)-binding peptide (VBP), collagenbinding peptide (CBP) and cyclic-Arg—Gly—Asp (cRGD)
peptide [107]. It was shown that liposomes containing
VBP and CBP could facilitate platelet-mimetic adhesion
and cRGD functionalized liposomes enhanced the aggregation of platelets onto themselves. Therefore, combination
of all three peptides provided a dual hemostatic function of aggregation and adhesion [107]. In another study,
Bertram et al. engineered functionalized nanoparticles
with the capabilities for binding to active platelets to
enhance their aggregation rate and consequently stop
bleeding [106]. A single emulsion evaporation technique was used to synthesize nanoparticles with the
diameter of 170 nm consisted of poly(lactic-co-glycolic
acid)-poly-L-lysine (PLGA-PLL) copolymer conjugated with
RGD functionalized PEG (Figure 2 A and B). The interaction of engineered nanoparticles with active platelets was
assessed in vitro by using a platelet adhesion and aggregation assay. These synthetic hemostatic nanoparticles also
reduced bleeding after intravenous injection in an injured
site in a rat artery by distributing throughout the clot
(Figure 2C—E). It was also shown that the nanoparticles were
effectively cleared within 24 h after infusion, demonstrating the potential application of the engineered hemostatic
nanoparticles for early intervention in trauma [106].
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Table 1
Traditional and nano-enabled adhesive materials.
Traditional surgical materials
Type
Components
Natural biomaterials
Fibrin-based
Fibrinogen, thrombin, and
CaCl2
CollagenBovine collagen, thrombin,
based
and plasma
Gelatinbased
Bovine gelatin, and
thrombin
Photocrosslinkable gelatin
Gelatin, and aldehyde, mTG
Gelatin, and poly(L-glutamic
acid)
Polysaccharides Chitosan powders and
photocrosslinkable chitosan
Synthetic biomaterials
Cyanoacrylate 2-octyl cyanoacrylate,
tantalum powder, and
n-butyl cyanoacrylate,
Polyurethanes Sprayable and
biodegradable polyurethane
PEG4-arm PEG with
based
glutaryl-succinimidyl ester
and thiol terminal groups
PEG ester and trilysine
amine solutions
Photocrosslinkable PEG
sealant
Synethic
musselbased
DOPA-PEG, -PCL, and
catechol-L-DOPA
Nano-enabled adhesive materials
Nanoparticles Silica nanoparticles
Cellulose nanocrystals
ZnO nanoparticles
Silver-based nanoparticles
Biomimetic
nanostructure
Formulation
Functionalities
Ref.
Fibrin clot formation
Hemostatic, sealant
[7,8,30—37]
Collagen clot formation
Hemostatic, sealant
[9,38—40]
Gelatin clot formation
Hemostatic, sealant
[41]
Photoinitiated
polymerization
Chemical crosslinking
using aldehyde
Crosslinking bonding
using water-soluble
carbodiimides
Photoinitiated
polymerization
Sealant
[10]
Hemostatic, sealant
[42]
Adhesives,
hemostatic
[34]
Adhesives,
antibacterial,
hemostatic
[43,44]
Addition polymerization:
anionic mechanisam
Adhesives, sealant
[12,13,51—54]
Addition polymerization
Aesorbable, non-toxic
tissue adhesive
Sealant
[1,15,62—64]
Stop cerebrospinal
fluid leakage
Stop air leaks, wound
closure, and
hemostasis
Hemostasis, and
wound closure
[56—58]
Adhesives
Adhesives
Antibacterial
Antibacterial,
adhesives, wound
closing, and
hemostatic
Antibacterial,
adhesives, lower
inflammatory
response, and tertiary
dentin formation
[22,23]
[96,100,110]
[119—121,130,131]
[115,123—127,129,132,133]
Adhesives
[137—142]
Adhesives
[145]
Adhesives
[147]
Covalent bonds
Photo or chemical
crosslinking
Photoinitiated
polymerization
Oxidation of catechol
groups to DOPA-quinone
Particle adsorption
Cellulose complexation
Zn complexation
Particle adsorption
Calcium phosphate-based
nanoparticles
Metal ion complexation
Hierarchical
mushroom-tipped nanoscale
fibrilsto
PCL patches covered with
microposts
Silicon nanowires on glass
beads
Combination of van der
Waals and capillary
forces
Layer of cyanoacrylate
medical glue
van der Waals forces
[26,55]
[16,59—61]
[69—83]
[120,122,123]
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Figure 1 Fabrication of hemostatic cationic hydrogel particles. (A) N-(3-aminopropyl)methacrylamide (APM) hydrogel particles
as hemostatic agents (scale bar: 5 mm in the SEM image and 500 ␮m in the inset). Images of a rat tail amputation (B) 5 min after
applying gauze showing bleeding and (C) 5 min after applying hydrogel particles showing bleeding was stopped. (D) Image from a
rat liver laceration incision, showing bleeding. (E) Image from hydrogel particles applied on liver, showing complete hemostasis
(reprinted from Ref. [105]).
Figure 2 Engineering synthetic nanoparticles with hemostatic properties. (A) Schematic of hemostatic nanoparticles made of
PLGA-PLL core with PEG arms terminated with the RGD. (B) SEM micrograph of nanoparticles (scale bar: 1 ␮m). (C) Femoral artery
injury model used to assess the in vivo function of hemostatic nanoparticles, arrow shows the injury site. (D) SEM image of clot
formed in an injured artery after the administration of nanoparticles, arrow shows the clot and fibrin mesh (scale bar: 1 ␮m). (E)
Cross section view of clot following artery injury and applying coumarin 6 (C6)-labeled nanoparticles (blue: DAPI-stained cell nuclei;
green: C6 from synthetic platelets within the clot) (reprinted from Ref. [106]).
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Hemostatic materials with nanofibrous structures have
been also developed for clinical applications [110,111]. For
example, Gu et al. produced chitosan-based nanofibrous
hemostatic mats with no acidic residual by using an electrospinning technique followed by neutralization [110]. The
intrinsic cationic properties of chitosan and its nonspecific binding to cell membrane led to the blood protein
adhesion, activation of platelets, and clot formation. The
engineered electrospun chitosan sheets were neutralized in
various alkali solutions after electrospinning to form nonacidic hemostatic mats. The blood clotting efficiency of
these nanofibrous hemostats, with fiber diameter in the
range of 350—440 nm, were then evaluated in vitro. The
adhesion of platelets and clot formation were higher on
the nanofibrous chitosan mats compared to both Surgicel
(an oxidized cellulose-based hemostatic agent) and chitosan
sponges [110]. Similarly, Luo et al. produced nanofibrous
hemostatic material based on self-assembling chiral peptide d-EAK16 [111]. In vitro erythrocyte aggregation assay
demonstrated the strong agglutinating activity when peptide concentration higher than 2.5 mg/ml was used. In
addition, it was shown that the nanofibrous peptides could
rapidly stop bleeding from an incision in a rabbit liver model,
demonstrating their suitability for clinical applications as
hemostatic materials [111].
Recently, nanoparticle solutions have been used as biological tissue adhesives and hemostatic materials [22,23].
For example, aqueous solutions of various nanoparticles
such as silica, carbon nanotube, and cellulose nanocrystals were used to connect pieces of hydrogels or tissues
together through the addition and absorption of nanoparticle solutions between the tissue pieces. It was shown
that solutions of silica nanoparticles could strongly glue two
pieces of calf’s liver, demonstrating the potential application of these nanoparticle solutions for surgical procedures
[22]. In another recent study, silica and iron oxide nanoparticles were used as hemostatic and wound closure materials
in skin and liver of a rat [23]. In this study, a polymeric
film was first coated by an aqueous solution of nanoparticles
to absorb nanoparticles onto its surface. The film was then
placed on a bleeding liver section. It was shown that particle
nanobridging could provide rapid adhesion and hemostasis
on the bleeding liver tissue [23]. These studies together
demonstrate that merging nanotechnology with advanced
tissue adhesives plays an important role in addressing unmet
clinical needs for hemostatic agents.
Antibacterial materials
With increasing concern about bacterial infections in the
injured sites, there is a growing need for the development
of tissue adhesives with antibacterial properties. Nanoparticles have been used as antibacterial agents for many clinical
applications due to their antibacterial effects on both gram
negative and gram positive bacteria [112]. Antibacterial
nanoparticles are classified into three groups including inorganic materials (e.g. metals [113], metal oxides [114], metal
salts [115]), organic nanocarrier (e.g. polymer and lipid)
loaded with antibacterial agents [116], and hybrid materials
[117]. Several methods such as chemical, physical, and biological synthesis have been used to produce antibacterial
nanoparticles for various clinical applications. It has been
shown that the stability, size, shape, morphology, and functionalization of these nanoparticles significantly affect their
antibacterial activities [118].
Antibacterial nanoparticles have been widely used as
dental adhesives. For example, the addition of 10%(w/v)
ZnO nanoparticles into dental composites was shown to
reduce the bacterial growth around 80%. Nanocomposite
dental adhesives composed of silver nanoparticles, ammonium dimethacrylate, and calcium phosphate nanoparticles
were also developed to facilitate mineralization and bacterial reduction [119]. It was shown that the fabricated
antibacterial nanocomposites decreased the metabolic
activity of Streptococcus mutans biofilms [119]. Similarly,
antibacterial nanocomposite adhesives based on calcium
phosphate nanoparticles, calcium fluoride nanoparticles,
and chlorhexidine were engineered to reduce the S. mutans
biofilm production and lactic acid formation [120]. In
another study, Ruiz et al. investigated the effect of nanoparticle size on antibacterial activity of dental adhesive against
S. mutans [121]. They found that decreasing the size of
nanoparticles from 98 nm to 9 nm significantly reduced the
growth of bacteria [121].
In a recent study, Li et al. used a rat tooth cavity model
to investigate the antibacterial activity and remineralizing restoration of an antibacterial bioadhesive containing
calcium phosphate nanoparticles and antibacterial dimethylaminododecyl methacrylate (DMADDM) [122]. It was found
that the bioadhesives containing both calcium phosphate
and DMADDM had lower inflammatory response and tertiary dentin formation compared to control groups without
or with one type of nanoparticles. The presence of calcium phosphate nanoparticles in these composites reduced
inflammation and enhanced tissue formation and the addition of DMADDM into composites promoted antibacterial
activity with no adverse effect on pulpal response [122].
In another study, Melo et al. developed antibacterial dental
adhesives containing calcium phosphate and silver nanoparticles. The fabricated dental adhesives enhanced bonding
strength to dentin and inhibited bacterial growth and acid
production in tooth cavity [123]. It was also found that incorporation of silver nanoparticles and calcium phosphate into
adhesive had no adverse effects on the bonding strength but
significantly enhanced antibacterial activities and remineralization of tooth lesions [123].
Antibacterial nanoparticles have been also incorporated
into tissue adhesives for wound protection and healing [115,124]. For example, nanocomposites composed of
genipin-crosslinked chitosan (GC), PEG, ZnO, and silver
nanoparticles were synthesized and used as antibacterial
tissue adhesives for wound healing [124]. It was shown
that the nanocomposites contained silver nanoparticles had
higher antibacterial activity compared with those without
silver nanoparticles [124]. In another study, Buckley et al.
showed that silver impregnated mesoporous hydroxyapatite
enhanced the production of silver phosphate antibacterial
nanoparticles against two bacteria, Staphylococcus aureus
and Pseudomonas aeruginosa, commonly present on the
wounds and skin [115]. Silver nanoparticles conjugated glucose and glycosaminoglycan were also used as antibacterial
bioadhesives for wound closing or as an antibacterial coating on surgical tools and catheter [125]. In another study,
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Figure 3 Development of an antibacterial hydrogel-based tissue adhesive. (A) Synthesis of an antibacterial hydrogel based on a
branched catechol functionalized PEG and silver ion. (B) TEM images of silver nanoparticles formed through the reaction between
silver ion and catechol functionalized PEG. (C) Cumulative silver release from the fabricated antibacterial hydrogel over two weeks
(reprinted from Ref. [132]).
antibacterial agents based on silver nanoparticle incorporated hyaluronan fibers were formed for wound closure
and healing [126]. Hyaluronan fibers were first formed
by using a wet spinning technique. The fibers were then
used as a capping and stabilizing agent to create silver nanoparticles through a chemical reduction of sliver
nitrate. The engineered fibers containing silver nanoparticles exhibited strong antibacterial activity against S. aureus
and Escherichia coli, demonstrating their capability for utilization as wound dressing bioadhesives [126]. In a recent
study, Wu et al. synthesized an antibacterial wound dressing
through the impregnation of silver nanoparticles on cellulose nanofibers. The engineered nanocomposite induced
99% reduction in P. aerudomonas, S. aureus and E. coli,
demonstrating its high antibacterial activity. The results
of in vitro studies also confirmed that silver nanoparticle
incorporated cellulose composites had no cytotoxicity to
cells, demonstrating their suitability as tissue adhesives for
wound dressing [127]. In another study, Guo et al. developed
an antibacterial bioadhesive for ocular treatment by incorporating moxifloxacin loaded poly(lactic-co-glycolic acid)
(PLGA) microparticles in a chondroitin sulfate (CS)/PEG
hydrogel [128]. Moxifloxacin incorporated PLGA nanoparticles with diameter less than 1 ␮m were produced by
using an electrospraying technique. The particles were then
loaded in CS/PEG hydrogel to form a bioadhesive containing
antibacterial particles with a controlled release rate of up
to 10 days. The developed antibacterial bioadhesive showed
great potential to be used as an antibiotic delivery for wound
healing in the eye [128].
Nanofibrous materials with antibacterial properties have
also been used as adhesive biomaterials for clinical applications such as wound dressings. The antibacterial properties
may stem from the employed polymers or from the incorporated antibacterial reagents. For example, Lakshman
et al. fabricated nanofibrous PU substrates containing silver
nanoparticles as an antibacterial wound dressing platform
[129]. In addition to suitable exudates management properties, the fabricated substrates could prevent the growth of
Klebsiella. In another example, Shalumon et al. fabricated
alginate/poly(vinyl alcohol) nanofibrous mats loaded with
ZnO nanoparticles [130]. The embedded ZnO nanoparticles
could inhibit the growth of S. aureus and E. coli. In another
instance, Cai et al. electrospun a mixture of chitosan and
silk fibroin to create nanofibrous substrates with antibacterial properties for wound dressings [131]. The antibacterial
activity of the fabricated substrates was assessed against
cultures of S. aureus and E. coli.
Inspired by mussel adhesive proteins, Fullenkamp et al.
recently synthesized an antibacterial hydrogel by using silver for spontaneous hydrogel formation through catechol
oxidation (Figure 3A) and as a precursor for the formation of
silver nanoparticles to give antibacterial properties to the
formed hydrogel [132]. Catechol containing PEG was used to
form the hydrogel and the polymer catechols were oxidized
by silver titrate for simultaneous hydrogel curing and reduction of silver ion. These reactions resulted in the formation
of round-shape nanoparticles with diameters that were up
to 50 nm (Figure 3B). It was found that silver release from
the hydrogel was sustained for at least two weeks in aqueous
solution (Figure 3C). The engineered antibacterial hydrogel
was shown to kill bacteria cells without reducing the viability of mammalian cells, demonstrating its capability to be
used as antibacterial tissue adhesives [132].
In a recent study, the mechanism of antibacterial activity
of ionic silver against Gram-negative bacteria was investigated [133]. The result of in vitro and in vivo tests showed
that silver disrupted multiple bacterial cellular processes,
which led to an increase in the formation of reactive oxygen species and membrane permeability permeation of the
Gram-negative bacteria [133]. In addition, the toxicity of
ionic silver in vivo was studied by determining a median
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Figure 4 Hierarchical topography of geckos sole. The topography is formed from microscale filament (setae), which branch into
nanoscale tips with mushroom-like heads (reprinted from Ref. [137]).
lethal dose (LD50) between 120 and 240 ␮M. The use of
silver nanoparticles for the development of antibacterial
tissue adhesives has attracted significant attention due to
their effective antibacterial activity. However, their potential toxicity should be considered for clinical applications.
Biomimetic nanostructured surgical materials
Living organisms have evolved over millions of years to
acquire skills to adapt to the environmental conditions and
to enhance their survival chance among other creatures.
Nature is filled with examples such as mussels, lizards, and
insects that rely on efficient adhesion to wet or dry surfaces for survival [134]. These natural models have been
inspiring scientists to develop new materials and strategies
to fabricate more effective tissue adhesives. In the previous sections, we discussed some of the naturally inspired
materials such as mussel protein adhesives and DOPA-based
glues. In this section, we will focus on the strategies that
utilize biomimetic nanotopography to enhance the adhesion force between the engineered tissue adhesives and the
surrounding tissues.
The reversible adhesion of gecko lizards to dry and
rough surfaces has fascinated scientists to understand this
adhesion mechanism and then adopt a similar strategy to
design dry adhesives [135,136]. Gecko’s soles contain arrays
of microscale fibers (setae) which in turn are split into
mushroom-tipped nanoscale fibrils (spatula) to form a hierarchical structure (Figure 4) [137]. A combination of van
der Waals and capillary forces at the contact area between
spatula and surface creates strong reversible adhesion (up to
10 N/cm2 ) [138]. To mimic these structures, micro and nanotechnologies have been utilized over the past few years
to create highly adherent surfaces [139]. Creating a geckoinspired topography requires a combination of the following
characteristics: (i) high aspect ratio structures (AR > 10); (ii)
slanted features to create anisotropic adhesion; (iii) structures with spatulate head; and (iv) hierarchical structures.
In addition, the employed materials should be flexible to
allow an increased contact area between the adhesive patch
and rough surfaces.
Murphy et al. also fabricated a hierarchical topography on the surface of a PU patch with an elastic modulus
of 3 MPa [140]. The PU surface was covered with slanted
mushroom head tipped microposts with 35 ␮m tip diameter and 100 ␮m long (Figure 5 A—C). Their results indicated
highly anisotropic behavior for posts with slanted tips. They
demonstrated that 1 cm2 of the patch could hold 1 kg weight
(∼10 N/cm2 ) in the gripping direction (Figure 5D) [140].
In another study, the same group fabricated a PU patch
with microscale slanted posts (600 ␮m tip diameter and
1.2 mm long) where their tips were covered by smaller
posts (112 ␮m tip diameter and 100 ␮m long) [141]. They
compared the adhesion force of patches containing double
level topography with the values for patches with and without single level posts (Figure 5E). Their results suggested
that the hierarchical structure increased the adhesion
force by almost six folds [141]. In another study, Jeong
et al. fabricated poly(urethane acrylate) (PUA) nanoscale
fibrils through replica molding with mushroom-like tips
[142]. Due to the formation of nanosized topography, they
achieved a shear adhesion of 25 N/cm2 , which was 10 times
higher than those reported by Murphy et al. Jeong et al.
also combined molding and surface wrinkling to create
stretchable and reversibly adhesive surfaces. They created poly(dimethylsiloxane) (PDMS) sheets covered with
posts through molding and then covered the tips with UV
crosslinkable PUA. They could achieve adhesion strength of
∼11 N/cm2 which was reversible and remained almost constant over 100 cycles of attachment and detachment [24].
The major difference between the operation of wet
adhesives and the dry adhesives discussed above is the wet
tissue environment in which gecko-inspired surfaces cannot adhere. In addition, tissue adhesives are meant to be
long lasting and have irreversible adhesion to the tissues.
Lee et al. developed the first gecko-inspired wet and dry
adhesives in which the surface of fibrous topography was
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Figure 5 SEM images of gecko-inspired surfaces. (A—C) Angled polyurethane (PU) posts with angled mushroom tips. The tip
orientation was changed at different angles: (A) 34◦ ; (B) 23◦ ; (C) 90◦ ; (D) 1 cm2 PU patch covered with angled posts supported 1 kg
weight (reprinted from Ref. [140]). (E) Two-level PU posts fabricated using molding to create hierarchical topography (reprinted
from Ref. [141]).
coated by poly(dopamine methacrylamide-co-methoxyethyl
acrylate) (pDMA-co-MEA) to mimic the adhesion mechanism
of mussels [66]. The patch was made from PDMS covered
with fibrils of 400 nm in diameter and 600 nm in length.
The adhesion force of pDMA-co-MEA coated fibrils in wet
condition was reported to be 86.3 nN in comparison to the
value of 5.9 nN for the non-coated ones. Glass et al. investigated synergic effect of surface topography and coating
with DOPA-based polymers for adhesion under wet conditions. They found that the DOPA-coating increased the
Figure 6 Gecko-inspired bioadhesives. (A) SEM images of a PGSA patch with nanopillars. (B) PGSA patch after 8 days of implantation
which confirms the stability of nanopillars in vivo (reprinted from Ref. [144]). (C) SEM image of PCL patch with micropillars coated
with cyanoacrylate. (D) A 3 mm diameter puncture in a rat colon. (E) Closure of the punctured region with the PCL patch. (F) Image
of a 3 mm defect created in rat stomach. (G) Successful implementation of the PCL patch for closing the defect (reprinted from
Ref. [145]).
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Figure 7 Porcupine quill-inspired tissue adhesives. (A, B) SEM images of barbless and barbed polyurethane quills (scale bar
500 ␮m). (C—E) Images showing the quills surface topography after removal from porcine skin. The topography creates mechanical
interlocking, which increases the pullout force of the quills from the skin (scale bar: 500 ␮m). (F,G) Adhesion test of a patch containing
barbless and barbed quills to porcine skin. The barbed quills improve the path attachment through mechanical interlocking (reprinted
from Ref. [149]).
adhesion force by two folds [143]. Mahdavi et al. developed another gecko-inspired tissue adhesive by generating
nanosized posts with diameters ranging from 100 nm to 1 ␮m
and heights of 0.8—3 ␮m on the surface of PGSA using a
molding process (Figure 6A) [144]. The surface of the fabricated patterns was coated by a thin layer of oxidized
dextran aldehyde (DXT) to promote bonding to the tissue. Shear adhesion tests on patterned PGSA and porcine
intestinal tissue showed a maximum separation force of
4.8 N/cm2 which was almost double of the value for flat
PGSA substrate. Their in vivo tests for the gecko-inspired
patches after two days of implantation indicated an adhesion force of 0.7 N/cm2 (Figure 6B). It was also shown that
the conformal contact between the adhesive patch and the
tissue could improve by increasing the distance between the
posts, which was somehow in contrast with their inspiration
from gecko soles [144]. Furthermore, in another example, Pereira et al. fabricated PCL patches covered with
microposts (base: 4.9 ␮m, length: 19.0 ␮m, pitch: 9.5 ␮m,
Figure 6C) [145]. A layer of cyanoacrylate medical glue was
then spin coated on the patterned patch. The adhesion
force of the patterned patches (∼2.5 N/cm2 ) was 2.6 times
higher than the value for unpatterned ones (∼1 N/cm2 ).
A minimal inflammatory response was observed following
three weeks implantation of the fabricated nanopatterned
patch in a rat model. The patch was also used for closing
colon and stomach punctures in rats (Figure 6D—G) [145].
In another study, Martinelli et al. fabricated buckypapers
(BP) with a highly porous fibrous microstructure from multiwalled carbon nanotubes (MWCNTs) [146]. The material was
very hydrophilic and its surface was quite rough with a maximum roughness height of 400 nm. They measured the shear
adhesion strength of the fabricated BP to a biological tissue, which was 20 mN/mm2 . This value was comparable to
the values for the gecko-inspired patch developed by Mahdavi et al. [144]. The high mechanical adhesion was related
to the material hydrophilicity which enhanced the capillary
forces, high porosity, and surface topography [146].
Gecko-inspired surfaces have also been used for designing tissue adhesive drug releasing capsules. In a recent
study, Fischer et al. grew silicon nanowires (60 nm
diameter) on the surface of 30—50 ␮m diameter glass beads
to increase their adhesion to mucosal epithelia [147]. In
addition to an increase in the van der Waals interaction between the particle surface and the tissue due to
presence of the nanotopography, the presence of nanostructured microvilli on the tissue could potentially further
enhance the adhesion strength. Upon incubation of coated
and non-coated beads with cells, authors reported almost
three times higher adherence due to nanotopography. The
results suggested that the use of nanopatterned microcapsules could potentially enhance the drug delivery efficiency
[147].
Bio-inspired adhesives are not limited to gecko-based
surfaces. There are many examples of living organisms,
which rely on strong attachment to surfaces. For example, Pomphorhynchus laevis is an endoparasite which inserts
its proboscis into the intestine wall of the host fish
and swells them to create high adhesion strength. This
observation inspired Yang et al. to fabricate a tissue
adhesive containing microneedles with swellable tips to
mechanically interlock with native tissue [148]. To form
the patch, a polystyrene (PS) core was first covered with a
layer of swellable polystyrene-block-poly(acrylic acid) (PSbPAA). Upon insertion of the needles into the tissue, the tip
absorbed liquid and swelled to mechanically interlock within
the tissue. The in vivo tests on the rat skin showed that the
swellable tips increased the removal force by seven times
(1.2 N/cm2 ) in comparison to the patches with regular PS
needles. The maximum adhesion strength to the intestinal
mucosal tissue was reported 4.5 N/cm2 which was 3.5 times
higher than the values for surgical staples. Moreover, the
swellable needles eliminated the chance of bacterial infiltration into the punctured hole which is a major challenge
in the use of surgical staples [148].
To develop biomimetic tissue adhesives, Cho et al.
mimicked the topography and shape of North American
porcupine quills tip that contains microscopic backward facing barbs (Figure 7A and B). They determined that the
penetration force for barbed quills was 54% less than the
value for barbless quills while its pull out force was three
times higher [149]. The increase in the pull-out force was
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due to mechanical interlocking of the barbs into the tissue. They fabricated PU barbed and barbless quills through
micromolding and the barbed ones required 35% less penetration force. They also observed a correlation between
the pull-out force and the number of dislocated barbs
(Figure 7C—E). Based on the easy tissue penetration and
strong adhesion force of the barbed quills, Cho et al. fabricated a biomimetic tissue adhesive containing an array
of microneedles. The fabricated PU patches with barbed
microneedles had a pull-out force of four times higher than
those with barbless needles and could maintain their conformal contact to the tissue (Figure 7F and G) [149].
In another example, Tsai and Chang investigated the
adhesion mechanism of water beetles to wet surfaces to
design auto-adhesive transdermal drug delivery patches
[150]. They fabricated PDMS patches with microposts of
2 ␮m in diameter and 2 ␮m in height. To mimic the secretion
by the insect to enhance the adhesion, they loaded silicon
oil within the PDMS molds and showed that an adhesion force
of 9.5 N/cm2 (normal load) and 5.0 N/cm2 (sheer load) was
achieved. The tissue adhesives discussed in this section can
be potentially used for closing punctures or wounds during
open surgeries, however, their utilization in minimally invasive surgeries is extremely challenging. Also, the significant
difference between the elastic modulus of the fabricated
patches and various soft tissues is another important challenge, which can prevent effective healing of the damaged
tissues. Although the use of other biocompatible materials
such as hydrogels which possess mechanical characteristics
similar to soft tissues can potentially solve this challenge,
the fabrication of high aspect ratio feature in soft materials
is extremely challenging.
Conclusion and future direction
During the last decades, synthetic or biological tissue adhesives that rely on in situ polymerizations and crosslinking
reactions have emerged as complementary techniques and
could address many challenges associated with sutures and
staples particularly in noninvasive surgeries. However, currently available tissue adhesives for clinical applications
have some limitations including toxicity, extensive swelling,
insufficient strength, and complex polymerization process.
In addition, the use of these polymer-based surgical materials requires specific storage and preparation conditions
before applying in vivo.
Recent advancements in nanotechnologies have touched
the field of tissue adhesives by either introducing new functionalities (e.g. hemostatic or antibacterial properties) or
improving their mechanical properties as well as their adhesion force to surrounding tissues. For example, recently it
has been shown that aqueous solution of nanoparticles can
act as connector to strongly bond tissue pieces together.
Rapid and strong adhesion by nanoparticle solutions can
be advantageous in very different clinical situations. For
instance, nanoparticle solutions can be easily applied for
wound closure and healing without the need for any specific
preparation or training. Nanoparticle solutions can be also
used to control bleeding in liver, kidney, and heart surgeries.
In addition, nanoparticles with antibacterial and hemostatic
properties have been incorporated into polymeric adhesives
13
to reduce the risk of infections or hemorrhage after surgeries. Tissue adhesives can potentially carry and release
various drugs at the injury site to facilitate the healing
process and tissue regeneration as well as to control the
inflammatory response. The utilization of drug nanocarriers
such as liposomes and nanoparticles allows prolonged and
sequential delivery of various drugs and factors. Therefore,
it is anticipated that by using such nanocarriers, multifunctional tissue adhesives can be synthesized, which are
specialized for a targeted tissue.
Creating artificial nanotopography that is inspired by
observations from nature has enabled scientist to create tissue adhesive patches with high adhesion properties. These
patches are prefabricated and can be used in a wide range
of open surgical operations. As a result, such patches cannot
be employed in laparoscopic surgeries or in blocking intrusions with severe hemorrhage. One potential direction of
the field is to create injectable adhesives that can crosslink
in situ and form nanotopography to enhance their adhesion
to surrounding tissues through van der Waals interaction or
mechanical interlocking.
Recent developments in nanofabrication techniques have
significantly contributed to the emergence of the field of
flexible and biodegradable electronics. One potential future
direction can be to combine polymeric tissue adhesives with
biodegradable electronics [151,152] to create smart tissue
adhesive. Such smart adhesive can monitor the healing process and the injury site environment for potential infections
and inflammations. Overall it is expected that by the new
functionalities added to tissue adhesives, they will be more
popular and can replace surgical staples and sutures in a
wide range of operations.
Acknowledgments
N.A. acknowledges the support from the National Health
and Medical Research Council (NHMRC, APP1037349). A.K.
acknowledges funding from the National Science Foundation
CAREER Award (DMR 0847287), the office of Naval Research
Young National Investigator Award, the National Institutes of Health (HL092836, DE019024, EB012597, AR057837,
DE021468, HL099073, EB008392), and the Presidential Early
Career Award for Scientists and Engineers (PECASE). A.T.
acknowledges the financial support of the Natural Sciences
and Engineering Research Council of Canada (NSERC). NAP
acknowledges funding from the National Science Foundation (CBET1033746) and the National Institutes of Health
(EB00246, EB012726) and the Gates Foundation (1007287).
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Please cite this article in press as: N. Annabi, et al., Nano Today (2014), http://dx.doi.org/10.1016/j.nantod.2014.09.006